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Pathophysiology of trigeminal autonomic cephalalgiastrigeminal autonomic cephalalgias

Jasna Zidverc‐TrajkovićHeadache center

The main features of the TACs:

1 Trigeminal distribution of the pain1. Trigeminal distribution of the pain

2. Ipsilateral cranial autonomic features

3. An (circadian) episodic pattern of attacks

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• Cavernous sinus is the only peripheral anatomical location where a single pathology could

A pathological focus on the cavernous sinus

where a single pathology could involve trigeminal C‐fibers andsympathetic fibers.

• Angiography during CH attack: localized narrowing ofACI distal to the carotid canal

Ekbom and Greitz 1970

• Hypothesis of intracavernous or systemic inflammation was not confirmed.

Schuh‐Hofer et al. 2006

Vascular changes in the cavernous sinus

• Migraine • Experimental pain • Cluster headache

The vascular change is driven by the trigeminal‐autonomic reflex , and thus is a marker of brain activation, not a cause of the syndrome.

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Trigeminovascular system

• Afferent fibers from cranial vessels and dura mater

• Bipolar cell bodies in trigeminal ganglion

• Central projections to the caudal brainstem or high cervical cord

Trigeminovascular system: responsible for pain

• Powerful vasodilator neuropeptides of TG:calcitonin gene‐related peptide ‐ CGRPsubstance Pneurokinin A

• Concentrations of CGRP are elevated during:spontaneous CH attacksglyceryl‐trinitrate‐provoked CH attacksmigraine attacksmigraine attacks

Goadsby and Edvinsson 1994, Fanciullacci et al. 1995

• CGRP is the marker of the activation of trigeminovascular system.

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Ophthalmic division of the trigeminal nerve

• Painful stimuli administered into the skininnervated by the V1: dilation of the ACI

May et al. 1998

innervated by the V3, or into the leg: no responsein the ipsilateral ACI,despite the experience of pain.

Pareja et al. 2001

• The ophthalmic division of trigeminal nerve producesreflex activation of the cranial parasympathetic outflow.

Trigeminal‐autonomic reflex

• Afferent limb is the ophthalmic division of the trigeminal nerve

• Cranial parasympathetic cells are in the SSN in the pons

• Efferent limb is facial/greater superficial petrosal nerve through the pterygopalatine ganglion.

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Trigeminal‐autonomic reflex

Concomitantly with the pain:

• The reflex activation of the parasympathetic outflow

• Vasoactive intestinal polypeptide VIP is the marker of this activation.

Activation of the cranial parasympathetic outflow

• Leads to:lacrimation,reddening of the eye

l inasal congestion…

• The cranial sympathetic fibers from the superior cervical ganglion destined to innervate the eye are compromisedganglion destined to innervate the eye, are compromised by carotid dilation or perivascular swelling as theytraverse the carotid canal.

The result is a partial Horner’s syndrome.

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The fundamental physiological facts relevant to primary headache syndromes.

• Ophthalmic division of trigeminal nerve will produce i l th ti t i ti ticranial parasympathetic autonomic activation.

migraine with cranial autonomic features 27‐73%

Barbanti et al. 2002, Gupta and Bhatia 2007,Obermann et al. 2007, Lai et al. 2009

• CH attack is a process involving trigeminal‐autonomicactivation.

Goadsby 2002

• Circadian timing

• Neuroendrocrine changes

A role of hypothalamus in CH

• Neuroendrocrine changes

• PET studies

• Hypothalamic DBS

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• Two significant peaks of CH, in July and January.

Kudrow 1987

Human clock system

• The general rise in frequency during the year was twice interrupted around the days when the clocks were put forward or back in spring and autumn.

b 0% f k f C• About 50% of attacks of CH occurat night.

Russell 1981

Melatonin:

• produced by the pineal gland • the rate of secretion has

Suprachiasmatic nucleus and melatonin

the rate of secretion hasa strong circadian rhythm

Moore 1997

• retino‐hypothalamic pathway (suprachiasmatic nucleus)

Hofman et al. 1996

• suprachiasmatic nucleusregulates the rate of melatonin secretion

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• The characteristic nocturnal peak of melatonin secretion is blunted during the active phase of cluster headache, and the excretion of its metabolite is abnormal.

Melatonin and CH

the excretion of its metabolite is abnormal.Waldenlind et al. 1987, Leone et al. 1998

• Melatonin in the preventive treatment of CHLeone et al. 1996, Peres and Rozen 2001

Other neuroendrocrine changes in CH

• Testosterone ↓

• Oestradiol

• Cortisol ↑, Ø phase shift

• Prolactin Ø circadian rhythm, ↑

• Growth hormone: bimodal peak

• response to TRH ↓

Kudrow 1977, Nelson 1978, Romiti et al. 1983, Waldenlind and Gustafsson 1987,Chazot et al. 1984, Polleri et al. 1982, Leone et al. 1990

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PET studies

• Activated areas:

areas generally associated with pain

an area that seems specific to CH

areas associated with vascular structures

PET studies: pain areas

• Anterior cingulateaffective response

F t l t d i l• Frontal cortex and insulae

• Ventroposterior thalamus contralateral

• Ipsilateral basal gangliarelate to movementrelate to movementthe wish to moveinhibition of movements

Derbyshire et al. 1997, Chudler and Dong 1995

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PET studies

Hypothalamic gray matter

• ipsilateral to the side of pain

• noted during CH attacknitroglycerin‐inducedspontaneous

• not activated between attacks

• different from areas activated• different from areas activatedin migraine (midbrain, pons)

May et al. 1998, Sprenger et al. 2004

MRI: voxel‐based morphometry

• The similar region hasincreased volume (increased neuronal density) of greymatter when CH patientswhere compared with controls.

May et al. 1999

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Neuroimaging in related syndromes

• The activation in the hypothalamic grey matter was found in 4 patients with spontaneous SUNCT

May et al. 1999, Sprenger et al. 2005, Cohen et al. 2004

• and in a patient suffering from atypical TAC.Sprenger et al. 2004

• The underlying cause of TAC might be similar, and the variation in duration and frequency might be generally dependent on a different disorder of the hypothalamic neurons or a different involvement of the trigeminovascular system.

Hemicrania continua

• A strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are then accompanied by autonomic y p yfeatures and migrainous symptoms.

Matharu et al. 2003, ICHD‐II

• Clinical presentation:overlap between TACs and migraine

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Hemicrania continua

• Contralateral posterior hypothalamus

• Ipsilateral dorsal rostral pons

I il t l t l t l idb i• Ipsilateral ventrolateral midbrain,the red nucleus, the substantia nigrabilateral pontomedullary junction.

Overlap with TACs and migraine

PET, n = 7Matharu et al. 2004

Hypothalamic activation

• Ipsilateral to the pain in CH• Ipsilateral, contralateral, bilateral or absent in SUNCT• Contralateral in PH• Contralateral in HC• Ipsilateral in trigeminal neuralgia• Bilateral in migraine• acute heat pain, response to pain

h diff i di f• There are different stereotactic coordinates of activated hypothalamic areas.

• NOT seen during experimentally induced pain by capsaicin

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Functional imaging data

• Primary headache syndromes can be distinguished on a

Weiller et al.2005

Primary headache syndromes can be distinguished on afunctional neuroanatomical basis by areas of activationspecific to the clinical presentation.

May 2005

Hypothalamic deep brain stimulation

• Intractable chronic CH

• 2000: the first DBS implant2000: the first DBS implant

• Ten years after (58pts):notable clinical improvement 60% complete control of attacks 30%

Leone et al. 2001, Leone et al. 2010

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PET study in CH patients with DBS

• Hypothalamic stimulation provoked activation in the ipsilateral trigeminal systemipsilateral trigeminal system.

• A functional connection inhumans

May et al. 2006

Trigeminohypothalamic tract

• A direct connection betweenthe trigeminal nucleus caudalis

d th t i h th land the posterior hypothalamus

• Sensory information from cranial skin, intracranial vessels and meninges reaches the hypothalamus via this tract.hypothalamus via this tract.

Malick et al. 2000

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Posterior hypothalamus and TCN • Orexin B injection into the PHincreases spontaneous TCN activityand heightens TCN responses to dural stimulation and noxious thermal stimulation of the face.

• Orexin A and the GABA‐A receptor antagonist bicuculline exert theopposite effects.

• The posterior hypothalamusis a physiological modulator of TCN activity.

Bartsch et al. 2004

PET study in CH patients with DBS

• Activation of the trigeminalsystem was NOT followed by CH attackCH attack.

• The trigeminal system activation is necessary for a CH attack to occur, but it is not sufficient on its own to evoke the attack.

May et al. 2006

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How DBS works?

The first hypothesis:

High frequency hypothalamic stimulation would inhibit hypothalamic hyperactivityhypothalamic hyperactivity.

Against this hypothesis:

• the latency of chronic stimulation (days or weeks)

• inefficacy of acute stimulation136 CH k i 16136 CH attacks in 16 pts.23% pts, 16% of attacks

Leone et al. 2006

DBS interfere with pain matrix

• Hypothalamic stimulation:ipsilateral trigeminal systemand pain matrixand pain matrixthalamus, somatosensorycortex, precuneus,anterior cingulate cortexthe middle temporal gyrus,posterior cingulate cortexand insula

May et al. 2006

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Hypothalamic DBS

• Modulation of the antinociceptive systemmodulates thermal sensitivity and increase pain thresholds

Jurgens et al. 2009g

• It could act by gradually restoring normal function and metabolism in hypometabolic areas in CH patients, eventually restoring deficient topdown modulation. odu a oSprenger et al. 2007

Hypothalamus

• Plays a major role in terminating rather than triggering attacks.

dLeone and Bussone 2009

• Regulating the duration of an attack, and the extent to which it does so would give rise to the different phenotypic expressions of the TACs which are principally distinguished by attack duration.principally distinguished by attack duration.

Leone et al. 2010

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Hypothalamic DBS for other TACs

• Severe drug‐resistant SUNCT was relieved by DBS.

Leone et al. 2005, Lyons et al. 2008

• A patient with chronic drug‐resistant PH has obtained long‐term relief with hypothalamic DBS.

Dafer, personal communication

Genetics related to hypothalamus

• The increased familial risk

• Hypocretin (orexin) receptor 2 (HCRTR2)yp ( ) p ( )the ability of this gene to modulate posterior hypothalamic neurons

Rainero et al. 2004, Schurks et al. 2006,

Baumber et al. 2006

• Despite the strong clinical indications of a geneticcomponent in CH, no specific genes have yet been clearlyassociated with this disorder.

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From cavernous sinus to pain matrix

Leone and Bussone 2009